Cleavage of α-Synuclein by Calpain:  Potential Role in Degradation of Fibrillized and Nitrated Species of α-Synuclein

• Published in: Biochemistry (Easton) Vol. 44; no. 21; pp. 7818 - 7829
• Main Authors: Mishizen-Eberz, Amanda J, Norris, Erin H, Giasson, Benoit I, Hodara, Roberto, Ischiropoulos, Harry, Lee, Virginia M.-Y, Trojanowski, John Q, Lynch, David R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 31.05.2005
• Subjects: alpha-Synuclein; Calpain - chemistry; Calpain - metabolism; Chymotrypsin - metabolism; Humans; Hydrolysis; Microscopy, Immunoelectron; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - ultrastructure; Nitrates - chemistry; Nitrates - metabolism; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Peptide Fragments - metabolism; Peroxynitrous Acid - chemistry; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Solubility; Synucleins; Tyrosine - analogs & derivatives; Tyrosine - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi047846q

α-Synuclein (α-syn) is a major protein component of the neuropathological hallmarks of Parkinson's disease and related neurodegenerative disorders termed synucleinopathies. Neither the mechanism of α-syn fibrillization nor the degradative process for α-syn has been elucidated. Previously, we showed that wild-type, mutated, and fibrillar α-syn proteins are substrates of calpain I in vitro. In this study, we demonstrate that calpain-mediated cleavage near and within the middle region of soluble α-syn with/without tyrosine nitration and oxidation generates fragments that are unable to self-fibrillize. More importantly, these fragments prevent full-length α-syn from fibrillizing. Calpain-mediated cleavage of α-syn fibrils composed of wild-type or nitrated α-syn generate C-terminally truncated fragments that retain their fibrillar structure and induce soluble full-length α-syn to co-assemble. Therefore, calpain-cleaved soluble α-syn inhibits fibrillization, whereas calpain-cleaved fibrillar α-syn promotes further co-assembly. These results provide insight into possible disease mechanisms underlying synucleinopathies since the formation of α-syn fibrils could be causally linked to the onset/progression of these disorders.